Invasive pulmonary aspergillosis, a common complication of immunosuppression, carries a strikingly poor outcome despite currently available therapy. While substantial work has evaluated the role of neutrophils in the lung's innate immune response to this pathogen, the role of other effector cells in host defense against this organism is less clear. Natural killer (NK) cells are a subset of lymphocytes important in immune responses against tumor cells, transplanted allogeneic cells, and several classes of micro-organisms. Our preliminary studies indicate that NK cells are critical to host survival in neutropenic mice with invasive aspergillosis and that their recruitment to the lung in the setting of this infection may be mediated by the CC chemokine ligand, MCP-1/CCL2. Moreover, NK cell-derived interferon-gamma (IFN-gamma) appears to augment fungal clearance from the lung. We therefore hypothesize that NK cells are integral components of innate host defense against invasive aspergillosis in neutropenic hosts, and that enhancing the recruitment of NK cells to the lung or augmenting their effector functions will improve the outcome of invasive aspergillosis. We shall address these hypotheses by examining the following Specific Aims in a murine model of invasive pulmonary aspergillosis: 1) To determine the in vitro activity of NK cells against Aspergillus and to determine their in vivo contribution to host defense in invasive aspergillosis; 2) To examine the role of the chemokine ligand, MCP-1/CCL2, and its receptor, CCR2, in the recruitment of NK cells to the lungs in invasive aspergillosis; and 3) To evaluate the role of NK cell-derived IFN-gamma in mediating anti-fungal host defense in vitro and in vivo. We hope that the proposed studies will provide important new insights into the role of NK cells as mediators of innate host defense in the lung in invasive aspergillosis, and that they will also result in development of novel therapies for this devastating infection.